Genetic Influence on Neurodevelopment in Nonsyndromic Craniosynostosis.
Genetic Influence on Neurodevelopment in Nonsyndromic Craniosynostosis.
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DOI：
10.1097/prs.0000000000008976
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发表时间：
2022-05-01
影响因子：
3.6
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中科院分区：
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非综合征性颅缝早闭症是颅面外科医生治疗的最常见的畸形之一。尽管有最佳的手术治疗，近一半的NSCS儿童有轻微的神经认知缺陷。尽管已经研究了手术干预的时机和类型对NSCS神经发育的影响，但遗传对神经发育的影响的可能性仍未探索。我们对404例散发性NSCS的病例父母三人组进行了全外显子组测序。进行了统计分析，以评估与预期和1，789例健康对照三人组相比，病例中从头突变的负担。分析了有和没有每种突变类型的个体，并记录了各种类型的神经发育延迟的存在或不存在，包括运动延迟，言语/语言延迟和智力残疾，以及人口统计学信息。我们发现，在NSCS先证者中，突变不耐受（pLI>0.9）基因的破坏性新生突变负担非常显著（P=5.9x10−6）。与没有这些突变的NSCS儿童相比，具有这些突变的儿童神经发育延迟的发生率高2倍（P=0.001），智力残疾的发生率高20倍（P=7.2x10−7），并且持续超过5岁的延迟可能性高3.6倍（P=4.4x10−4）。高pLI基因中的传递性功能丧失突变也使神经发育延迟的风险增加1.9倍（P=4.5x10−4）。这些发现暗示遗传病变同时影响神经发育和颅形态发生的神经干细胞综合征的病因，并确定了一个强大的遗传影响神经发育的结果在受影响的儿童。这些发现最终可能被证明是有用的，以确定哪些儿童与神经干细胞最有可能受益于手术干预。
Non-syndromic craniosynostosis (NSCS) is one of the most common anomalies treated by craniofacial surgeons. Despite optimal surgical management, nearly half of children with NSCS have subtle neurocognitive deficits. Whereas the impact of timing and type of surgical intervention on neurodevelopment in NSCS has been studied, the possibility of genetic influence on neurodevelopment remains unexplored. We performed whole exome sequencing for 404 case-parent trios with sporadic NSCS. Statistical analyses were performed to assess the burden of de novo mutations in cases compared to both expectation and 1,789 healthy control trios. Individuals with and without each mutation class were analyzed, and the presence or absence of various types of neurodevelopmental delay, including motor delays, speech/language delays, and intellectual disability, were recorded alongside demographic information. We identified a highly significant burden of damaging de novo mutations in mutation intolerant (pLI>0.9) genes in NSCS probands (P=5.9x10−6). Children with these mutations had a 2-fold higher incidence of neurodevelopmental delay (P=0.001), >20-fold greater incidence of intellectual disability (P=7.2x10−7), and were 3.6-fold more likely to have delays that persisted past 5 years of age (P=4.4x10−4) in comparison to children with NSCS without these mutations. Transmitted loss of function mutations in high pLI genes also conferred a 1.9-fold greater risk of neurodevelopmental delay (P=4.5x10−4). These findings implicate genetic lesions concurrently impacting neurodevelopment and cranial morphogenesis in the pathoetiology of NSCS, and identify a strong genetic influence on neurodevelopmental outcomes in affected children. These findings may eventually prove useful in determining which children with NSCS are most likely to benefit from surgical intervention.